1. Field of the Invention
The present invention relates to the use of topically administered S(+) ibuprofen to prevent or treat erythema induced by ultraviolet irradiation in mammalian organisms in need of such prevention or treatment, and to certain topical pharmaceutical compositions comprising unit dosage effective amounts of S(+) ibuprofen.
2. Description of the Prior Art
Ibuprofen, or (+) 2-p-isobutylphenyl)propionic acid, has the structural formula ##STR1##
The compound is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity. Ibuprofen is currently marketed by prescription in the United States generically, as well as under tradenames such as Motrin.RTM., which is available in 400, 600 and 800 mg tablets for oral administration. Ibuprofen has recently also become available in this country in non-prescription strength (200 mg) under a variety of tradenames, including Advil.RTM. and Nuprin.RTM., as well as in generic form. For the treatment of mild to moderate pain, 400 mg every 4 to 6 hours, not to exceed 3200 mg daily, is generally recommended for Motrin.RTM.. The lower dose over-the-counter products are generally recommended for minor aches and pains, to be used orally at the 200 to 400 mg level, every 4 to 6 hours, not to exceed 1200 mg daily unless directed by a physician. See also Physician's Desk Reference, 40th edition, 1990, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, NJ 07649.
As is apparent from its chemical nomenclature, ibuprofen is a racemic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been some studies of the individual S(+) and R(-) isomers reported in the literature. These generally reflect that the R(-) isomer is converted in vivo but not in vitro to the S(+) enantiomer, which is the active form of ibuprofen.
Adams et al, Curr. Med. Res. Opin., 3, 552 (1975) and J. Pharm. Pharmacol. 28, 256-257 (1976), reported that in vivo anti-inflammatory and analgesic tests in guinea pigs, rats and mice comparing the dextro (+), levo (-) and racemic mixture forms of ibuprofen showed the three forms to be very similar in potency. (The in vivo tests were conducted in an acetylcholine-induced writhing test in the mouse, in a pain threshold technique test using the yeast-inflamed paw of the rat and using ultraviolet erythema in the guinea pig.) In vitro however, it was found that nearly all of the activity resided in the dextrorotatory form. The authors concluded that the in vitro results suggested that only the dextro (+) form was the active one, but that in vivo the levo form was converted to the dextro form so that there was little difference in pharmacological activity. This was also seen to be an explanation for earlier observations [Adams et al, J. Pharm. Sci., 56, 1686 (1967) and Mills et al, Xenobiotica, 3, 589-598 (1973)] that ibuprofen's urinary metabolites in man were found to be dextrorotatory. Thus, it has been recognized for over a decade that the S(+) isomer is the active form.
Wechter et al, Biochem. Biophys. Res. Commun., 61, 833-837 (1974) reported the results of tests in healthy human subjects designed to determine the stereochemistry involved in ibuprofen's metabolism and the relative stereochemical relationships between ibuprofen's optical isomers and its metabolic products. They found there was a facile epimerization of ibuprofen's R(-) isomer to the S(+) isomer and concluded that this accounted for the essential bioequivalence of the R(-) and S(+) isomers.
Related observations were reported by Vangiessen et al, J. Pharm. Sci., Vol 64, No. 5, 798-801 (May 1975), who found that after oral administration of the racemic mixture to human volunteers, the predominant enantiomer in the peripheral circulation and excreted in the urine was of the d-configuration. Vangiessen et al estimated that the plasma drug disappearance half-lives for the d- and 1-isomer were 3.34 and 2.01 hours, respectively. The concentration ratio of d to 1 increased progressively with time from 1.17 at one hour to 2.65 at eight hours; however, these estimates are compromised by the small sample size (n=3), the fact that normal subjects were used, and the extremely large standard deviations from the mean at the earliest (one-hour) postdosing time point. Interpretation of the results of this study is further compromised because S(+) was not administered alone so that no comparisons with the racemate are possible.
Subsequently, Kaiser et al., J. Pharm. Sci., Vol. 65, No. 2, 269-273 (February 1976) reported on characterization of enantiomeric compositions of ibuprofen's major urinary metabolites after oral administration of the racemic mixture and the individual S(+) and R(-) isomers to healthy human subjects. It was found that only the R(-) enantiomer of the intact drug was inverted to its optical antipode, S(+).
Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed the earlier work on the metabolic chiral inversion of 2-arylpropionic acids, including ibuprofen, which they indicate was the first substituted 2-arylpropionic acid conclusively shown to undergo the inversion as well as the most studied member of the group. The authors again noted that Adams et al (1976) found no significant difference in in vivo activity among the R(-) and S(+) isomers and the racemic mixture in three different animal models, but very large differences in vitro between the R(-) and S(+) isomers, ascribing this discrepancy to the virtually quantitative conversion of the R(-) to the active S(+) isomer in vivo. Hutt et al indicated similar properties for fenoprofen. The enantiomers of fenoprofen were reported to be of equal potency in animal test systems.
In the same paper, Hutt et al reported that, in contrast, for several other 2-arylpropionic acids, the inactive R(-) isomer was not converted in vivo to the active S(+) isomer as readily as ibuprofen and fenoprofen, although the conversion seemed to occur to some extent over time. Naproxen, they noted, has been the only compound marketed as the S(+) enantiomer to date. And in the case of indoprofen, the R(-) enantiomer was found to be about 20 times less pharmacologically active in rats and mice in vivo than the S(+) isomer. Hutt et al concluded:
It is likely that benefits will be obtained from the use of the S(+)-enantiomer of 2-arylpropionates as drugs as opposed to the racemates. This is only found at present in the case of naproxen. In cases of rapid inversion, the inactive R(-) isomer serves merely as a prodrug for the active S(+)-antipode. Where inversion is slow, the R(-) enantiomer is an unnecessary impurity in the active S(+) form. Use of the S(+)-enantiomer would permit reduction of the dose given, remove variability in rate and extent of inversion as a source of variability in therapeutic response and would reduce any toxicity arising from non-stereospecific mechanisms.
Thus, in cases of rapid inversion, such as ibuprofen and fenoprofen, where substantially equivalent in vivo responses have been reported for the individual enantiomers and the racemic drug, Hutt et al suggested that no benefits would be obtained from the use of the S(+) isomer because the inactive R(-) isomer merely acts as a prodrug for the active S(+) form. Contrariwise, in cases where chiral inversion is slow, e.g., naproxen and indoprofen, the use of the S(+) enantiomer is desirable for several reasons enumerated by Hutt et al. Indeed, naproxen has been reported to be marketed as the d-isomer for one of the reasons given by Hutt et al, i.e., to reduce side effects (Allison et al, "Naproxen," Chapter 9 in Anti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsford and Path, CRC Press Inc., Boca Raton, FL., 1985, p. 172).
Another general report on earlier work has been provided by Hutt et al in Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on the importance of stereochemical considerations in the clinical pharmacokinetics of 2-arylpropionic acids, the authors tabulated relative potencies of the enantiomers of a number of 2-arylpropionic acids in vivo and in vitro. The in vitro results showed the S or (+) isomer in each case to be the active species. In vivo, however, the results were not consistent across the entire class. Thus, the results for naproxen and indoprofen demonstrate the S or (+) isomer to be much more active in vivo, indicating a relatively slow inversion of the inactive R or (-) isomer to the active S or (+) isomer; the results for fenoprofen and ibuprofen, on the other hand, demonstrate the inactive R or (-) and the active S or (+) isomers to be approximately equally effective in vivo. indicating a rapid inversion of R or (-) isomer to S or (+) isomer.
The medicinal chemistry of 2-arylpropionic acids and other NSAIDs (non-steroidal anti-inflammatory drugs) has been reviewed by Shen in Angewandte Chemie International Edition, Vol. 11, No. 6, 460-472 (1972) and in "Nonsteroidal Anti-Inflammatory Agents," Chapter 62 in Burger's Medicinal Chemistry, 4th edition, part III, Wiley Interscience, New York (1981), pp. 1205-1271. In the former publication, Shen notes that ibuprofen is used as a racemic mixture because the two optical isomers are equally potent in the UV erythema assay, a commonly used anti-inflammatory model.
Lee et al, Br. J. Clin. Pharmac. 19, 669-674 (1985), administered racemic ibuprofen and each of the enantiomers separately to four healthy human males, then studied stereoselective disposition. They estimated that about 63% of the dose of R(-) was inverted to the S(+) enantiomer over a 14 hour period. Lee et al noted that the kinetics of the S(+) and R(-) enantiomers were changed when the respective optical antipode was concurrently administered. The authors speculated that this alteration reflected an interaction between the R(-) and S(+) forms at the binding sites for plasma protein. An ibuprofen plasma level time profile for a single subject is shown graphically in the paper and might suggest that there was minimal conversion in the early hours of the study, but the authors did not appear to attach any significance to this. Lee et al indicated that the half-life of S(+) after administering the racemate was 2.5 hours, whereas the half-life of S(+) after administering S(+) was 1.7 hours. The authors recognized the limitations of their work, for reasons including the small number of subjects studied, and an assumption that the clearance of S(+) is unchanged between administrations of R(-) and S(+). They also cautioned that it is quite likely that the fraction of R(-) that is inverted to S(+) varies from individual to individual.
Cox et al, J. Pharmacol. Exp. Ther., Vol. 232, No. 3, 636-643 (1985), carried out liver perfusion experiments to study the role of the liver in the clearance of the stereoisomers of ibuprofen in normal and disease states. Experiments were conducted with normal and fatty rat liver. Results showed that when liver is fatty, clearance of the R(-) isomer is affected and preferential S(+) hepatic distribution is eliminated. However, the effects were predicted to have only minimal impact on total ibuprofen plasma levels following racemic ibuprofen dosing.
Cox et al, abstract in Amer. Soc. Clin. Pharmacol. Ther., February 1987, 200 (abstract PIIL-7) described a three way crossover study in which single doses of ibuprofen solution were given orally to twelve healthy human males. The doses given were 800 mg of racemic ibuprofen, 400 mg of R(-) ibuprofen and 400 mg of S(+) ibuprofen. Based on area-under-the-curve measures, significant chiral inversion was observed for R(-) but not for S(+). Elimination of S(+) was inhibited as plasma concentration of R:S increased. The extent of R(-) inversion, based on urinary data, was the same for the racemate and the R(-) isomer, with a mean of .66. Again, the authors gave no information as to what occurred in the first two hours. The statement on reduced clearance of S(+) in the racemate is consistent with the finding of increased length of S(+) half-life after administering the racemate found by Lee at al.
Laska et al, Clin. Pharmacol. Ther., Vol. 40, No. 1, 1-7 (July 1986), reported that administration of racemic ibuprofen to patients with moderate to severe pain subsequent to third molar extraction gave correlations between pain intensity ratings and serum levels of ibuprofen. Correlations were found between contemporaneous serum levels and measures of pain intensity improvement, supporting the proposition that increased ibuprofen serum levels lead to increased analgesia, particularly in the first few hours after dosing. However, the authors did not correlate analgesia with either isomer of ibuprofen; the possibility of critical differences between free and bound ibuprofen and between the S(+) and R(-) isomers was not addressed.
A considerable amount of effort has been spent in the search for a method to prevent the occurrence of, or alternatively, to treat sunburn. Sunburn is caused by certain wavelengths of ultraviolet (UV) radiation striking the skin. The ultraviolet light alters the keratinocytes in the basal layer of the epidermis. A slight alteration results in erythema, and a severe alteration causes bullae to form from the fluid collected in the epidermis. To produce a suntan, ultraviolet light stimulates the melanocytes in the germinating layer to generate more melanin and oxidizes melanin already in the epidermis. Both of these processes serve as protective mechanisms by diffusing and absorbing additional UV radiation. The effects of the sun on the skin usually begin to appear anywhere from 1 to 24 hours after exposure and range from mild erythema to tenderness, pain, and edema. Severe reactions due to excessive exposure involve the development of vesicles or bullae as well as the constitutional symptoms of fever, chills, weakness, and shock.
Energy emissions from the sun include radiation wavelengths ranging from 200 nm to more than 18,000 nm. Ultraviolet radiation is in the 200-400 nm range, and this spectrum is subdivided into three bands.
UV-A (320-400 nm) radiation can cause tanning of the skin, but is weak in causing mild sunburn of the skin. Erythemic activity (producing redness) is relatively weak at this wavelength. The primary action of UV-A is the development of a slow natural tan. At this UV level, radiation produces some immediate pigment darkening. In addition, UV-A represents the range in which most photosensitizing chemicals are active. It is also believed that UV-A may augment the effects of UV-B.
UV-B (290-320 nm) radiation causes sunburn reaction, which also stimulates pigmentation (tanning) of the skin. It is the most effective UV radiation wavelength for producing erythema, which is why it is called sunburn radiation. It triggers new pigment formation as well as vitamin D production. In addition, it is thought to be responsible for inducing skin cancer.
UV-C (200-290 nm) radiation from sunlight does not reach the earth's surface, but artificial UV sources can emit this radiation. It does not tan the skin, but it can burn it. UV-C radiation from the sun does not reach the surface of the earth. However, UV-C is emitted by artificial ultraviolet sources. Although it will not stimulate tanning, it causes some erythema.
Other wavelengths of light also are absorbed and, if intense enough, produce erythema and burning. This type of burning differs from sunburn in that it is due to generated heat rather than a photochemical reaction.
Thus, it has been well documented that excessive exposure to ultraviolet light will cause erythema, edema, blister formation and sloughing of the skin due to cellular damage. Ultraviolet light injury includes epidermal cell death, increase in mitotic index, hyperplasia, as well as the vascular responses of vasodilation, altered permeability and cellular exudation.
The vascular changes that occur secondary to exposure to ultraviolet light are biphasic. The immediate erythema reaction is a faint, transient reddening of the skin beginning shortly after exposure to ultraviolet light and fading within 30 minutes after the exposure ends. A delayed erythema reaction appears after 2-6 hours and peaks 10-24 hours after ultraviolet-light exposure. This erythema gradually subsides over the next 2-4 days. Peeling follows 4-7 days after a moderate to severe sunburn. The mechanisms by which these two types of erythema are produced are not understood completely. Kinins, histamine, prostaglandins, other vasoactive substances, hydrolytic enzymes, and free radicals have been implicated as mediators of the erythema caused by sunlight.
Prostaglandins have been shown to increase in erythematous skin exposed to ultraviolet B radiation. Aspirin and indomethacin which are nonsteroidal anti-inflammatory agents have been shown to inhibit the prostaglandin synthetase system in skin.
Snyder et al, "Intradermal Anti-Prostaglandin Agents and Sunburn," The Journal of Investigative Dermatology, Vol. 62, No. 1, 47-50 (1974) discussed the intradermal administration of indomethacin as well as aspirin to guinea pigs. The administration of each of those drugs was shown to decrease the intensity and delay the development of ultraviolet radiation induced erythema. Snyder et al, "Topical Indomethacin and Sunburn," British Journal of Dermatology, pp. 90-91 (1974), further demonstrated that the topical application of indomethacin in humans produced a reduction in redness, skin temperature and pain perception. It was suggested that indomethacin may be affecting sunburn by preventing biosynthesis of prostaglandins.
Likewise, several nonsteroidal anti-inflammatory drugs have been administered orally to human subjects and have been demonstrated to be effective in reducing erythema after exposure to ultraviolet radiation. In particular, Edwards et al, "Reduction of the Erythema Response to Ultraviolet Light by Nonsteroidal Anti-inflammatory Agents," Arch. Dermatol. Res., Vol. 272, pp. 263-267, studied the effect of orally administered aspirin, indomethacin and ibuprofen on ultraviolet B induced erythema in human subjects. All three drugs were comparable in reducing the sunburn response to ultraviolet radiation.
Gomez et al, "Effect of Topical Diflumidone on Ultraviolet-Light-Induced Erythema," Dermatologica, Vol. 162, pp. 175-182 (1981) studied the topical efficacy of indomethacin and diflumidone for the suppression of ultraviolet-light-induced erythema in humans. Both indomethacin and diflumidone were found to inhibit the development of erythema; however, the indomethacin treated sites had significantly less erythema 24 hours after application.
Greenberg et al, "Orally Given Indomethacin and Blood Flow Response to UVL," Arch. Dermatol., Vol. 111, pp. 328-330 (March 1975), demonstrated that orally administered indomethacin reduced the increase in blood flow produced by ultraviolet light irradiation by one-third.
Lim et al, "Effect of Indomethacin on Alteration of ATPase-Positive Langerhans Cell Density and Cutaneous Sunburn Reaction Induced by Ultraviolet-B Radiation," Journal of Investigative Dermatology, Vol. 81, No. 5, pp. 455-458 (1983), showed that indomethacin topically applied prior to ultraviolet-B irradiation in humans resulted in protection from the sun. Topical application of indomethacin after ultraviolet-B irradiation resulted in a decrease in erythema. The protective effect of topical indomethacin applied prior to radiation may be explained by its in vitro absorption of ultraviolet-B irradiation. The application of indomethacin after irradiation resulting in decreased erythema was probably related to its effect on prostaglandin synthetase inhibition. The authors concluded that indomethacin applied topically could be useful as a sunscreen agent. Its clinical safety and efficacy, however, remain to be determined.
Flowers et al, "A Comparative Study of the Effect of Flurbiprofen and Indomethacin on Sunburn," Current Therapeutic Research, Vol. 36, No. 4, pp. 787-791 (October 1984), evaluated the efficacy of ultraviolet-B induced erythema in humans when the subjects were treated with a test solution containing 2.5% indomethacin, 2.5% flurbiprofen or vehicle alone. The authors concluded that flurbiprofen showed more promise than indomethacin in the suppression of early ultraviolet-B irradiation induced erythema.
Tas et al, "Effect of Topically Applied Flurbiprofen on Ultraviolet-Induced Erythema," Drug Intelligence and Clinical Pharmacy, Vol. 20, 496-499 (1986), studied the effect of flurbiprofen on ultraviolet-B induced erythema in humans. The authors concluded that topical flurbiprofen decreased the dermal symptoms of sunburn. The optimum maximum concentration of flurbiprofen appeared to be approximately 3% and more than two applications appeared to have no added advantage.
In summary, the current state of the art recognizes that, in mammals, the S(+) form is the active enantiomer of ibuprofen. The art further recognizes that there is a significant, relatively rapid conversion in vivo of R(-) to S(+), with little, if any, conversion of S(+) to R(-). Furthermore, in the only animal experiments on efficacy reported in the literature, it was noted that there were no significant differences in potency between the racemate and the enantiomers in vivo. This is attributed to the rapidity of the chiral inversion. This would suggest there would be no benefit to be derived from the use of S(+) ibuprofen for any purpose. Indeed, use of S(+) alone would appear to reduce the half-life of the active drug. The prior art, moreover, is conspicuously silent in respect to any prevention or alleviation of sunburn utilizing any particular optical isomer of the ibuprofen drug species. The prior art is silent on conversion of the R(-) isomer to the S(+) isomer by the skin.